Abstract
BackgroundCisplatin has been widely used for the treatment of cancer and its antitumour activity is attributed to its capacity to form DNA adducts, predominantly at guanine residues, which impede cellular processes such as DNA replication and transcription. However, there are associated toxicity and drug resistance issues which plague its use. This has prompted the development and screening of a range of chemotherapeutic drug analogues towards improved efficacy. The biological properties of three novel platinum-based compounds consisting of varying cis-configured ligand groups, as well as a commercially supplied compound, were characterised in this study to determine their potential as anticancer agents.MethodsThe linear amplification reaction was employed, in conjunction with capillary electrophoresis, to quantify the sequence specificity of DNA adducts induced by these compounds using a DNA template containing telomeric repeat sequences. Additionally, the DNA interstrand cross-linking and unwinding efficiency of these compounds were assessed through the application of denaturing and native agarose gel electrophoresis techniques, respectively. Their cytotoxicity was determined in HeLa cells using a colorimetric cell viability assay.ResultsAll three novel platinum-based compounds were found to induce DNA adduct formation at the tandem telomeric repeat sequences. The sequence specificity profile at these sites was characterised and these were distinct from that of cisplatin. Two of these compounds with the enantiomeric 1,2-diaminocyclopentane ligand (SS and RR-DACP) were found to induce a greater degree of DNA unwinding than cisplatin, but exhibited marginally lower DNA cross-linking efficiencies. Furthermore, the RR-isomer was more cytotoxic in HeLa cells than cisplatin.ConclusionsThe biological characteristics of these compounds were assessed relative to cisplatin, and a variation in the sequence specificity and a greater capacity to induce DNA unwinding was observed. These compounds warrant further investigations towards developing more efficient chemotherapeutic drugs.
Highlights
Cisplatin has been widely used for the treatment of cancer and its antitumour activity is attributed to its capacity to form DNA adducts, predominantly at guanine residues, which impede cellular processes such as DNA replication and transcription
It is of interest to characterise the DNA binding properties of all of these compounds regardless of their cytotoxicity since this may aid the identification of their structural attributes that are either beneficial or an impediment to their possible clinical potential
A compound may be highly reactive to purified DNA but may possess structural properties that hinder its capacity to reach DNA in a cellular environment
Summary
Cisplatin has been widely used for the treatment of cancer and its antitumour activity is attributed to its capacity to form DNA adducts, predominantly at guanine residues, which impede cellular processes such as DNA replication and transcription. Intrastrand DNA adducts between adjacent G residues account for 60% of Located at the ends of chromosomes are G-rich telomere sequences consisting of tandem repeats of 5′-TTAGGG(n)-3′ [9]. These undergo shortening during progressive rounds of normal cell replication that limits. Cisplatin-induced DNA adducts have the ability to bend and locally unwind the DNA helix to cause unstacking of the guanines [15] and to kink DNA by 53° [16] These adducts are recognised by enzymes including those involved with DNA repair [17], such as the nucleotide excision repair proteins [18, 19]. DNA lesions may be shielded by HMG box 1 proteins [20, 21] that protect them from repair and this may be a key factor contributing to their antitumour efficiency
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